The current fungal meningitis crisis is a tragedy, but one that could have been avoided if clear warning signs had been heeded. To understand the risks we have been running, we need to understand clearly the differences in controls and intents between GMP pharmaceutical manufacture of sterile products and a pharmacy compounding “sterile” products. These differences are reflected in the regulation of pharmaceutical manufacturing by 21 CFR 211 (GMP) vs the regulation of compounding pharmacies by individual states relying on USP <797> “Pharmaceutical Compounding – Sterile Preparations” as the source document. The fundamentally different approaches to preparation of sterile product taken reflects the different purposes – the GMP is designed to ensure a reproducible, stable drug product suitable for interstate commerce and storage, the pharmacist’s preparation is meant for for immediate use, made in small amounts for a specific patient in response to a doctor’s script. This basic difference in intent has led, predictably, to this situation as externally sourced “compounding pharmacies” have begun to manufacture in batch sizes up in the thousands of units for national distribution.
According to a recent ISMP Medication Safety Alert, the 2008 revision of the US Pharmacopeia (USP) Chapter <797> left many facilities unable to meet the published standards for sterile compounding. It is true that this revision tightened up the expectations for the relaxed pharmacy practices associated with sterile compounding prior to this point. That this minimal level of expected cleanroom maintenance and process control should render pharmacies flummoxed is worrisome as a separate consideration. However, the ISMP alert goes on to state that the resultant escalation in drug shortages (presumably because pharmacies were no longer compounding sub-par medications) led to a steady increase in external sterile compounding pharmacy services. According to this article, 66% of all hospital pharmacies that participated in a 2011 survey outsource some portion of their sterile compounding. In other words, it is implied that the minimal requirements for patient safety in USP <797> from 2008 led directly to this crisis.
It is important to remember that the revision to USP <797> was in fact sparked by the obvious problems in sterile pharmacy compounding practices. Now, it is the assumption that a pharmacy is compounding for an individual patient with a specific doctor’s script to guide the compounding. The use of the medication will be relatively rapid, not allowing time for low levels of bacterial contamination to proliferate in the “sterile” compound. This understanding is implicit in the recognition of three different levels of “sterile” medications, rated according to risk and likelihood of microbial proliferation (Low-, Medium-, and High Risk Compounded Sterile Products). It is well established that even the best of conditions in a “sterile” pharmacy compounding process is highly prone to contamination , especially compared to GMP pharmaceutical manufacturing facilities. It must be noted that this splitting of “sterility” into different categories of “sterile” is fundamentally different from the GMP pharmaceutical manufacturing approach of Quality by Design for sterile drug product which requires process validation and control yielding a sterile product stable for extended periods.
A second interesting argument has recently been put forward. In a recent Wall Street Journal article, it was implied that a faulty “sterility test” was to blame for release of the tainted medication from NECC. This position is inaccurate, as no sterility test available can actually test for product sterility (as was noted in the same WSJ article). It is the robustness of the manufacturing process that serves as the Quality standard for sterile products.
The real problem is with the system of allowing the poor manufacturing and quality practices of pharmacies to produce large scale batches of medications that will not be used immediately, thus allowing microbial proliferation in the “sterile” container. This point is also made by the recent ISMP Medication Safety Alert mentioned above. Pharmacies have no GMP tradition, nor, at least seemingly in the current case in the news, at best a minimal concern about manufacturing cleanliness and contamination control. They do (at least at the national level) seem very concerned about maintaining their prerogative “that compounding is a traditional right of pharmacists.” FDA is clearly not to blame here, as consistent efforts to get this situation under control have been stymied by a Congress concerned about “excess government regulation” and the courts.
Pharmacies have no business operating as manufacturing facilities, and we have had plenty of warning before this crisis. FDA reported in 2007 that the Agency had reports of 200 adverse events at that time involving 71 compounded products since 1990. The general public has been made aware of some examples as well – a few of which are outlined below. As you review these events, please also note that many involve shipment across state lines, and sometimes extremely large batch sizes.
- 33 people across 7 states contracted fungal endophthalmitis leading to the recall of 6 months’ worth of all compounded batches from Franck’s Pharmacy. This pharmacy also produces veterinary products (40% of 2009 sales).
- Oto-Ease ear lubricant (a non-sterile product) was recalled due to potentially pathogenic microbial contamination.
- More than 300 patients contracted fungal meningitis after receiving methyl-Prednisolone acetate injection prepared by NECC (the current crisis related to compounding pharmacies).
- 9 patients died of the 19 total taken ill in Alabama when parenteral nutrition solutions that were administered were contaminated with Serratia marcescens during compounding using non-sterile components to prepare amino acids. The compounding pharmacy, Meds IV, was found to have the same strain of S. marcescens in the tap water faucet and the compounding equipment.
- 16 people in Florida and Tennessee infected when a compounding pharmacy in Hollywood, CA repackaged Avastin for off-label eye injections. Contaminated intra-ocular injections for age-related macular degeneration resulted in blindness for some.
- Eight cases of Sphingomonas paucimobilis bloodstream infections were associated with contaminated intravenous fentanyl.
- Up to 25 patients in New Jersey and California contracted Serratia marcescens infections due to contaminated magnesium sulfate prepared by Pharmedium, a compounding pharmacy located in Lake Forest, IL.
- 6 cases of postsurgical endophthalmitis were reported due a compounded trypan blue ophthalmic injection contaminated with Pseudomonas aeruginosa and Burkholderia cepacia. This was recalled by the compounding pharmacy Custom-RX of Richfield, MN.
- 10 patients died in Virgina after exposure to cardioplegia solution from 2 lots contaminated with gram-negative rods. This product was made by Central Admixture Pharmacy Services, Inc. (CAPS), a subsidiary of B. Braun Medical located in Maryland (also see 1998 incident below).
- Pseudomonas putida septicemia was reported in a special care nursery due to contaminated flush solutions prepared in a hospital pharmacy.
- 36 cases of Pseudomonas fluorescens bloodstream infections were associated with a heparin/saline flush. From the MMWR Report: “To produce its heparin/saline flush, IV Flush ordered heparin powder and sent it to a compounding pharmacy, where a concentrated heparin solution was made. This concentrated solution was then returned to IV Flush, where it was added to bags of saline solution, from which the syringes were filled.” IV Flush was located in Rowlett, Texas while the affected patients were in four states across the country. A later research paper identified potentially 80 cases.
- 36 patients developed Pseudomonas bloodstream infections after receiving heparin/saline flushes from multiple lots of preloaded syringes by Pinnacle Medical Supply of Rowlett, TX. These infections occurred in Missouri, New York, Texas, and Michigan.
- 2 patients reported with life-threatening sepsis caused by Burkholderia cepacia from contaminated intravenous flush solutions that had been shipped across state lines.
- 16 patients were reported with Hepatitis C virus infections from a contaminated radiopharmaceutical used in myocardial perfusion studies.
- Bacteria contamination with Burkholderia cepacia found in at least 2 batches of a compounded inhalant solution used by 19,000 patients nationwide with chronic lung diseases. Med 4 Home (Kansas City, MO) did only a partial recall of the batches, which totaled more than 1-million doses.
- North & South Carolina MMWR reported on Exophiala infections from contaminated injectable methyl-Prednisolone prepared by a compounding pharmacy; one patient died. NOTE that this report describes fungal meningitis from a steroid spinal injection.
- Injectable methylprednisolone and baclofen was recalled by FDA recommendation because of contamination with Penicillium mold, Methylobacterium, and/or Mycobacterium chelonae. This recall was later expanded to all products of Urgent Care Pharmacy due to poor manufacturing quality.
- 11 patients contracted Serratia marcescens infections following the injection of betamethasone compounded at a community pharmacy in California.
- 4 children contracted Enterobacter cloacae infections from IV ranitidine compounded in a hospital pharmacy.
- 13 patients (3 fatalities) came down with bacterial meningitis after receiving contaminated betamethasone shots prepared by Docs Pharmacy in California.
- Med-Mart Pulmonary Services of California was forced to recall five lots of Albuterol (an inhalant) due to contamination by Serratia liquefaciens.
- Survey of compounded Alprostadil formulations from a variety of sources showed contamination in 18% of samples tested.
- 11 children became septic in California and 10 tested positive for Enterobacter cloacae bloodstream infections associated with contaminated prefilled saline syringes from CAPS, Braun-McGaw of Detroit, MI. (see also 2005 incident above).
- Four patients died of an Enterobacter infection from a filter-sterilized cardioplegia solution (a parenteral with high potential for bacteremia) compounded in a Nebraska hospital. In this episode five bottles of the solution tested were nonsterile, several subsequent bottles tested were sterile, and another 93 bottles were dispensed without being tested.
- 2 patients lost their vision after becoming infected by Pseudomonas aeruginosa found in indomethacin eye drops compounded in a Pennsylvania drug store.